EP2297110B1 - Indanderivate als modulatoren des ampa rezeptors - Google Patents

Indanderivate als modulatoren des ampa rezeptors Download PDF

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EP2297110B1
EP2297110B1 EP20090757548 EP09757548A EP2297110B1 EP 2297110 B1 EP2297110 B1 EP 2297110B1 EP 20090757548 EP20090757548 EP 20090757548 EP 09757548 A EP09757548 A EP 09757548A EP 2297110 B1 EP2297110 B1 EP 2297110B1
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mmol
alkyl
dihydro
inden
methyl
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EP2297110A1 (de
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Jonathan Gillespie
Craig Jamieson
John Kinnaird Ferguson Maclean
Elizabeth Margaret Moir
Zoran Rankovic
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Merck Sharp and Dohme BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/08—Antiepileptics; Anticonvulsants
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/20—Hypnotics; Sedatives
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to heterocyclic derivatives, to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular to their use for the treatment or prevention of psychiatric diseases where an enhancement of synaptic responses mediated by AMPA receptors is required.
  • L-glutamate is the most abundant excitatory neurotransmitter located in the mammalian central nervous system (CNS). L-glutamate plays a significant role in the control of cognition, mood and motor function and these processes are imbalanced in psychiatric and neurological disorders.
  • the physiological effects of glutamate are mediated through two receptor families, the metabotropic (G-protein coupled) receptors and the ionotropic (ligand-gated ion channels) receptors.
  • the ionotropic receptors are responsible for mediating the fast synaptic response to extracellular L-glutamate.
  • the ionotropic glutamate receptors are separated into three subclasses on the basis of molecular and pharmacological differences and are named after the small molecule agonists which were originally identified to selectively activate them: AMPA ( ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid), NMDA ( N -methyl-D-aspartate) and kainate (2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine).
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid
  • NMDA N -methyl-D-aspartate
  • kainate (2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine.
  • the importance of AMPA receptors in brain physiology is widely recognised and it has been shown that AMPA receptors control the majority of fast excitatory amino acid transmission in the CNS and also contribute to synaptic plasticity playing a role in a variety
  • AMPA receptor subunits are encoded by four distinct genes (termed GluR1 to 4), each representing proteins of around 900 amino acids.
  • the individual sub-units consist of a large extracellular N-terminal domain, an extracellular ligand binding site for L-glutamate formed by domains designated S1 and S2.
  • the transmembrane domain consists of three transmembrane regions, M1, M3 and M4 together with the re-entrant loop M2. This is then followed by a long intracellular C-terminal domain.
  • All four AMPA receptor subunits contain so-called 'flip' and 'flop' splice variants which differ in alternate slicing of 38 amino acid encoding exons (differing by less than 10 amino acids) in the S2 extracellular domain. Further heterogeneity of the AMPA receptors results from RNA editing, the most significant being the Q/R site located in the pore region (M2) of the GluR2 subunit.
  • the R variant which a large proportion of native GluR2 subunits are believed to comprise, is characterised by significantly reduced calcium permeability.
  • a further R/G editing site is located in the S2 domain of GluR2, GluR3 and GluR4 with the G form exhibiting an acceleration in the kinetics of recovery from desensitisation.
  • the kinetics of desensitisation and deactivation are important functional properties of the AMPA receptor that control the magnitude and duration of the synaptic response to glutamate.
  • the processes of desensitisation and deactivation can be modulated by AMPA receptor positive allosteric modulators that bind remotely from the agonist binding site, yet influence agonist binding, or indeed agonist mediated conformational changes in the receptor associated with gating and/or desensitisation. Consequently there are continued efforts to develop drugs that specifically target these properties and which will have therapeutic potential in the treatment of a wide variety of CNS disorders associated with diminished glutamatergic signalling. Examples of these conditions include age-related memory impairment, Alzheimer's Disease, Parkinson's Disease, depression, psychosis, cognitive defects associated with psychosis, attention deficit disorder and attention deficit hyperactivity disorder.
  • AMPA receptor modulators A variety of structural classes of compounds which act as AMPA receptor modulators (see G. Lynch, Current Opinion in Pharmacology, 2006, 6, 82-88 for a recent review).
  • AMPA receptor modulators see G. Lynch, Current Opinion in Pharmacology, 2006, 6, 82-88 for a recent review.
  • benzamide compounds related to aniracetam see A. Arai et al., J Pharmacol Exp. Ther., 2002, 30, 1075-1085
  • benzothiadiazine derivatives such as S-18689
  • B. Pirotte J Med. Chem., 1998, 41, 2946-2959
  • the biarylpropylsulfonamide derivatives see P.L. Ornstein et al., J Med. Chem. 2000, 43, 4354-4358 .
  • AMPA receptor modulators Another class of AMPA receptor modulators was disclosed in International Patent Appplications WO 2005/040110 and WO 2005/070916 which detail various heterocyclic compounds as being of utility as glutamate modulators. Further classes of compounds indicated to potentiate the glutamate receptor and their uses in medicine are disclosed in WO 2006/015828 and WO 2006/015829 . Compounds in each of these classes exhibit varying degrees of potentiation of the AMPA receptor.
  • WO 2002/060874 relates to a series of potassium channel inhibitors indicated to be especially useful for the treatment of cardiac arrhythmias and cell proliferative disorders.
  • WO 2005/105759 relates to substituted tetrahydropyridopyrimidine and tetrahydroquinazoline compounds and to their use as medicines.
  • the present invention relates to a heterocyclic derivative according to formula I wherein
  • C 1-6 alkyl represents a branched or unbranched alkyl group having 1-6 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl, tertiary butyl and n-pentyl.
  • C 1-4 alkyl represents a branched or unbranched alkyl group having 1-4 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl and tertiary butyl.
  • C 2-6 alkenyl represents a branched or unbranched alkenyl group having 2-6 carbon atoms and at least one double bond. Examples of such groups are ethenyl and isopropenyl.
  • C 2-6 alkynyl represents a branched or unbranched alkynyl group having 2-6 carbon atoms and at least one triple bond. Examples of such groups are ethynyl and propynyl.
  • C 3-8 cycloalkyl represents a branched or unbranched cyclic alkyl group having 3-8 carbon atoms. Examples of such groups are cyclopropyl, cyclopentyl and 2-methylcyclohexyl.
  • C 3-8 cycloalkylC 1-2 alkyl represents a C 1-2 alkyl group which is substituted with a C 3-8 cycloalkyl group. Examples of such groups are cyclopropylmethyl, and 2-cyclobutylethyl.
  • C 1-6 alkyloxy represents a branched or unbranched alkyloxy group having 1-6 carbon atoms. Examples of such groups are methoxy, ethoxy, isopropyloxy and tertiary butyloxy.
  • C 6-10 aryl represents an aromatic group having 6-10 carbon atoms and comprising one ring or two rings fused together, at least one of which must be aromatic. Examples of such groups include phenyl and naphthyl.
  • halogen represents a fluorine, chlorine, bromine or iodine.
  • solvate refers to a complex of variable stoichiometry formed by a solvent and a solute (in this invention, a compound of formula I). Such solvents may not interfere with the biological activity of the solute.
  • suitable solvents include, water, ethanol and acetic acid.
  • Examples of 5 to 9 membered heteroaryl ring systems comprising 1-2 heteroatoms selected from O, S and N include furan, pyrrole, thiophene, imidazole, pyrrazole, thiazole, pyridine, pyrimidine, indole, indazole and benzthiophene.
  • Examples of 4 to 6 membered saturated or unsaturated heterocyclic ring optionally comprising another heteroatom selected from O, S and N include pyrrole, imidazole, pyrrazole, thiazole, pyridine piperidine morpholine and piperazine.
  • L 1 can be attached to the five membered heteroaryl ring containing X 1 -X 3 at either X 1 or X 2 .
  • R 3 and L 2 can be attached to the fused bicyclic ring at any of the methylenes of said fused bicyclic ring and that R 3 and L 2 can be attached to the same or different methylene.
  • L 1 is O or NR 5 , wherein R 5 has the previously defined meanings.
  • L 1 is CO or SO 2 .
  • L 1 is (CR 6 R 7 ) m , wherein R 6 , R 7 and m are selected independently and have the previously defined meanings.
  • L 1 is CH 2 or CH 2 CH 2 .
  • L 1 is CH(CH 3 ).
  • L 1 is CH 2 .
  • L 2 is NHSO 2 or SO 2 NH
  • L 2 is N(CH 3 )SO 2 or SO 2 N(CH 3 ).
  • L 2 is NHSO 2 .
  • R 1 is C 1-4 alkyl or CN, said C 1-4 alkyl being optionally substituted with 1-3 halogens.
  • R 1 is trifluoromethyl.
  • R 1 is isopropyl, tertiary-butyl or CN.
  • R 1 is SO 2 CH 3 or NHSO 2 CH 3 .
  • R 2 is C 1-4 alkyl, or C 1-4 alkyloxy, said C 1-4 alkyl and C 1-4 alkyloxy being substituted with halogen, OH, C 1-4 alkyloxy or NR 18 R 19 , wherein R 18 and R 19 are selected independently and have the previously defined meanings.
  • R 2 is methyl substituted with halogen, OH, C 1-4 alkyloxy or NR 18 R 19 , wherein R 18 and R 19 are selected independently and have the previously defined meanings.
  • R 2 is -CH 2 OH, -CH 2 CH 2 OH or - CH(CH 3 ) 2 OH.
  • R 2 is C 1-4 alkyl substituted with amino, methylamino or dimethylamino. In a further embodiment, R 2 is aminomethyl, CH 2 N(CH 3 ) 2 , (CH 2 ) 2 N(CH 3 ) 2 or (CH 2 ) 2 NH(CH 2 ) 2 OH. In a further embodiment, R 2 is C 1-4 alkyl substituted with halogen. In a further embodiment, R 2 is CF 3 or CH 2 F.
  • R 3 is H, C 1-6 alkyl or C 1-6 alkyloxy. In a further embodiment, R 3 is H, C 1-4 alkyl or C 1-4 alkyloxy. In a further embodiment, R 3 is H or methyl. In a further embodiment, R 3 is H.
  • R 4 is H, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-2 alkylC 3-8 cycloalkyl or NR 28 R 29 , wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more halogens.
  • R 4 is H, C 1-4 alkyl, C 3-8 cycloalkyl or C 1-2 alkylC 3-8 cycloalkyl wherein said C 1-4 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more halogens.
  • R 4 is methyl, ethyl, isopropyl or tertiary-butyl, wherein said methyl, ethyl, isopropyl and tertiary-butyl are optionally substituted with one or more halogens.
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
  • R 4 is amino, NHCH 3 , N(CH 3 ) 2 , NHCH 2 CH 3 or NH(CH 2 CH 3 ) 2 .
  • R 4 is piperidine, pyrrolidine, morpholine or 4-methylpiperazine.
  • R 4 is C 6-10 aryl or a 5-9 membered heteroaryl ring system comprising 1-2 heteroatoms independently selected from O, S and N, wherein said C 6-10 aryl and 5-9 membered heteroaryl ring system are optionally substituted with one or more moieties independently selected from halogen, C 1-6 alkyl, hydroxy or C 1-6 alkyloxy, said C 1-6 alkyl and C 1-6 alkyloxy being optionally substituted with 1-3 halogens.
  • R 4 is an aryl or heteroaryl group selected from phenyl, thienyl, pyrrolyl, thiazolyl, furanyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl and pyrimidyl, said aryl or heteroaryl group being optionally substituted with methyl, trifluoromethyl, methoxy or halogen.
  • R 4 is phenyl or thienyl, said phenyl or thienyl being optionally substituted with halogen, C 1-4 alkyl or C 1-4 alkyloxy.
  • R 4 is phenyl or thienyl, said phenyl or thienyl being optionally substituted with halogen, methyl or methoxyl.
  • the fragment is selected from: wherein R 1 and R 2 are selected independently and have the previously defined meanings.
  • the fragment is selected from: wherein R 3 , L 2 and R 4 are selected independently and have the previously defined meanings.
  • the fragment is selected from: wherein L 2 and R 4 are selected independently and have the previously defined meanings.
  • heterocyclic derivative selected from: and or a pharmaceutically acceptable salt or solvate thereof.
  • heterocyclic derivatives of the present invention are prepared by methods well known in the art of organic chemistry. See, for example, J. March, 'Advanced Organic Chemistry' 4th Edition, John Wiley and Sons . During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P.G.M. Wutts 'Protective Groups in Organic Synthesis' 2nd Edition, John Wiley and Sons, 1991 . The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.
  • arylcycloalkylamines ( 2 ) may be halogenated with, for example, bromine in water, to give bromoarylcycloalkylamines ( 3 ).
  • arylcycloalkylamines ( 3 ) may be halogenated with, for example, bromine in water, to give bromoarylcycloalkylamines ( 3 ).
  • a suitable organic base such as 1,1,1-diazabicycloundecane (DBU), to give the sulphonamide ( 4 ).
  • DBU 1,1,1-diazabicycloundecane
  • the compound ( 1 ), wherein L 1 is methylene can be prepared starting from the precursor ( 5 ), wherein L 1 -LG is a methoxycarbonyl group by reduction of ( 5 ) with, for example, lithium aluminium hydride in tetrahydrofuran to give the intermediate alcohol (wherein L 1 -LG is hydroxymethyl).
  • This can then be readily chlorinated with a suitable chlorinating reagent such as thionyl chloride to provide the intermediate alkylchloride (wherein L 1 -LG is chloromethyl), which in turn can be reacted with a suitably functionalised heterocycle ( 6 ) in the presence of a suitable base, for example potassium carbonate to provide the desired adduct ( 1 ).
  • L 1 -LG could be an acid chloride moiety (i.e., L 1 as CO and LG as Cl) and the heterocycle ( 6 ) could be a 2-lithiopyrrole, prepared, for example, by reaction of 2-bromopyrrole with n-butyllithium.
  • heterocyclic derivatives of formula I can alternatively be prepared using an analogous process to that of Scheme 1 but with the steps carried out in a different order. Hence, it is possible to prepare compounds of the type ( 11 ) as adumbrated in Scheme 2 .
  • the present invention also includes within its scope all stereoisomeric forms of heterocyclic derivatives according to the present invention resulting, for example, because of configurational or geometrical isomerism.
  • stereoisomeric forms are enantiomers, diastereoisomers, cis and trans isomers etc.
  • R 2 is 1-hydroxyethyl the compound exists as a pair of enantiomers.
  • R 3 is methyl both cis and trans geometric isomers are possible.
  • the present invention includes the aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than 2% and in particular less than 1 % of the other stereoisomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present invention.
  • chiral compounds For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g ., synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Chirality In Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley ). Likewise methods for synthesis of geometrical isomers are also well known in the art.
  • the heterocyclic derivatives of the present invention in the form as a free base, are isolated from reaction mixtures as pharmaceutically acceptable salts. These salts are also obtained by treatment of said free base with an organic or inorganic acid, for example, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, ciric acid, benzoic acid and ascorbic acid.
  • an organic or inorganic acid for example, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, ciric acid, benzoic acid and ascorbic
  • heterocyclic derivatives of the present invention also exist as amorphous forms. Multiple crystalline forms are also possible. All these physical forms are included within the scope of the present invention.
  • solvates Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004 ) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004 ); and A. L. Bingham et al, Chem. Commun., 603-604 (2001 ).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the present invention also embraces isotopically-labelled compounds of the compounds described and claimed herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C 14 C 15 N 18 O 17 O, 31 P, 32 P, 35 S 18 F, and 36 Cl, respectively.
  • Certain isotopically-labelled compounds of Formula I are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula (I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • a prodrug is a compound which acts as a drug precursor which, upon administration to a subject, undergoes conversion by metabolic or other chemical processes to yield a heterocyclic derivative of formula I or a solvate or salt thereof.
  • R 2 is hydroxymethyl the hydroxyl group may be capped as, for example, an ester or a carbamate, which upon administration to a subject will undergo conversion back to the free hydroxyl group.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series , and in Bioreversible Carriers in Drug Design, (1987) Edward B.
  • heterocyclic derivatives of the present invention and their pharmaceutically acceptable salts and solvates are useful in therapy.
  • the heterocyclic derivatives of the present invention are useful for the manufacture of a medicament for the treatment or prevention of psychiatric diseases where an enhancement of synaptic responses mediated by AMPA receptors is required.
  • heterocyclic derivatives are useful for the manufacture of a medicament for the treatment of neurodegenerative disorders, cognitive or memory dysfunction, memory and learning disorders, attention disorder, trauma, stroke, epilepsy, Alzheimer's disease, depression, schizophrenia, psychotic disorders, anxiety, autism, a disorder or disease resulting from neurotic agents, substance abuse, alcohol psychiatric disorders, Parkinson's Disease, sleep disorders or narcolepsy or other conditions resulting from sleep deprivation.
  • the present invention further includes a heterocyclic derivative for use in the treatment of any of the aforementioned diseases or disorders.
  • a heterocyclic derivative for use in the treatment of neurodegenerative disorders, cognitive or memory dysfunction and memory and learning disorders.
  • a heterocyclic derivative for use in the treatment of Alzheimer's disease is a heterocyclic derivative for use in the treatment of Alzheimer's disease.
  • the present invention further includes a method for the treatment of a mammal, including a human, suffering from or liable to suffer from any of the aforementioned diseases or disorders, which comprises administering an effective amount of a heterocyclic derivative according to the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • effective amount or therapeutically effective amount is meant an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • a heterocyclic derivative of the present invention or a pharmaceutically acceptable salt or solvate thereof, also referred to herein as the active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient and the particular disorder or disease being treated.
  • a suitable daily dose for any of the above mentioned disorders will be in the range of 0.001 to 50 mg per kilogram body weight of the recipient (e.g . a human) per day, preferably in the range of 0.01 to 20 mg per kilogram body weight per day.
  • the desired dose may be presented as multiple sub-doses administered at appropriate intervals throughout the day.
  • the present invention therefore also provides a pharmaceutical composition comprising a heterocyclic derivative according to the present invention in admixture with one or more pharmaceutically acceptable excipients, such as the ones described in Gennaro et. al., Remmington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000 ; see especially part 5: pharmaceutical manufacturing.
  • suitable excipients are described e.g ., in the Handbook of Pharmaceutical Excipients, 2nd Edition; Editors A. Wade and P.J.Weller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1994 .
  • Compositions include those suitable for oral, nasal, topical (including buccal, sublingual and transdermal), parenteral (including subcutaneous, intravenous and intramuscular) or rectal administration.
  • the mixtures of a heterocyclic derivative according to the present invention and one or more pharmaceutically acceptable excipient or excipients may be compressed into solid dosage units, such as tablets, or be processed into capsules or suppositories.
  • solid dosage units such as tablets, or be processed into capsules or suppositories.
  • the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g., a nasal or buccal spray.
  • dosage units e.g., tablets
  • the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated.
  • any pharmaceutically acceptable additive can be used.
  • the compounds of the invention are also suitable for use in an implant, a patch, a gel or any other preparation for immediate and/or sustained release.
  • Suitable fillers with which the pharmaceutical compositions can be prepared and administered include lactose, starch, cellulose and derivatives thereof, and the like, or mixtures thereof used in suitable amounts.
  • aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
  • the present invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
  • the addition funnel was rinsed with MeOH (13.3 mL) and rinsings added to reaction. The mixture was stirred at 60 - 65 °C for 10 min until a clear solution was obtained. The reaction was then allowed to cool to room temperature and stirred for a total of 4 h. The solids were collected by filtration and washed with a pre-cooled mixture of isopropyl acetate/ methanol 2:1 (2 x 15mL) followed by water (2 x 15mL). The crude product was dried in a vacuum oven at 50 °C overnight to yield (18.03 g) of a fluffy white solid.
  • Tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (0.014 mmol, 14.17 mg) was dissolved in THF (1 mL) and triphenylphosphine (0.027 mmol, 7.18 mg) added. The mixture was stirred at room temperature for 30m before addition of N -bromosuccinimide (0.027 mmol, 4.87 mg).
  • a 150 mL steel autoclave was charged with N -(5-bromo-2,3-dihydro- 1H -inden-1-yl)propane-2-sulfonamide (4.85 g, 15.24 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.622 g, 0.762 mmol), and sodium carbonate (3.23 g, 30.5 mmol) in degassed methanol.
  • the autoclave was placed under carbon monoxide atmosphere (12 bar) and stirred at 100 °C for 24 hr.
  • lithium aluminium hydride (2.102 mL, 5.04 mmol) was added dropwise to a stirred solution of methyl 1-(1-methylethylsulfonamido)-2,3-dihydro- 1H -indene-5-carboxylate (1 g, 3.36 mmol) in tetrahydrofuran (dry) (25 mL). Mixture warmed to rt and stirred for 4 hr.
  • reaction mixture was warmed to room temperature and stirred for a further 30 min before an additional 0.2ml of di-isobutyl aluminium hydride was added and stirring continued for 30 min before quenching with MeOH followed by water.
  • the mixture was concentrated before partitioning between EtOAc/water. The aq. layer was acidified with 5N HCl until all solids were in solution. The organic phase was collected, dried and concentrated and the residue purified by HPLC to give a colourless oil which crystallised on standing (63 mg, 0.151 mmol, 77 %).
  • the compounds in this invention may be tested using a biological assay which measures Ca 2+ influx mediated through positive modulation of the AMPA (GluR1) receptor using standard techniques in the art such as, but not limited to, a FLEXstation (manufactured by Molecular Devices, Sunnyvale, CA). An optical readout using fluorescent probes is employed to measure ion channel dependent changes in intracellular ion concentration or membrane potential.
  • the assay utilises the Ca 2+ conductance of functional homomeric GluR1(i) AMPA receptors to generate glutamate-dependent Ca 2+ responses.
  • Influx of Ca 2+ through the ion channel is measured indirectly through an increase in intracellular Ca 2+ levels using the calcium sensitive dye such as, but not limited to, Fluo-3 (Molecular Devices, Sunnyvale, CA) in FLEXstation.
  • the calcium sensitive dye such as, but not limited to, Fluo-3 (Molecular Devices, Sunnyvale, CA) in FLEXstation.
  • a positive AMPA receptor modulator, in the presence of glutamate, will result in an influx of Ca 2+ through the ion channel which can be measured indirectly through an increase in intracellular Ca2+ levels using the calcium sensitive dye Fluo-3 in FLEXstation.
  • HEK.GluR1(i) cells were maintained in DMEM supplemented with 10% fetaclone II, 1% non-essential amino acids and 150 ⁇ g/ mL hygromycin, at 37oC/5% CO2. Twenty-four h prior to the assay, the cells were harvested with trypsin and seeded onto Costar 96 well clear bottomed black plates at a density of 3.5x10 4 per well.
  • Cells were loaded with 5 ⁇ M fluo3-AM in DMEM media in the absence of hygromycin and incubated at 37°C/5% CO 2 for one h. After dye loading, the cells were washed once with 200 ⁇ l of low calcium solution (10 mM hepes, pH 7.4, 160 mM NaCl, 4.5 mM KCI, 2 mM CaCl 2 , 1 mM MgCl 2 , 10 mM glucose) containing 0.625 mM of probenecid (inhibitor for the anion-exchange protein) to remove the dye. Then 200 ⁇ l of low calcium solution was added to each well.
  • low calcium solution 10 mM hepes, pH 7.4, 160 mM NaCl, 4.5 mM KCI, 2 mM CaCl 2 , 1 mM MgCl 2 , 10 mM glucose
  • the Flexstation added 50 ⁇ l of glutamate +/- test compound in high calcium solution (10 mM Hepes, pH 7.4, 160 mM NaCl, 4.5 mM KCI, 20 mM CaCl 2 , 1 mM MgCl 2 and 10 mM glucose) to each well and the ensuing response was monitored on FLEXstation.
  • the compounds of this invention exhibit positive modulation of the AMPA receptor having EC 50 values in the range 0.3 ⁇ M to 30 ⁇ M. For instance, Example 18 gave an EC 50 of 2.5 ⁇ M.
  • the recording chamber contained 1-2 ml extracellular solution (145 mM NaCl, 5.4 mM KCI, 10 mM HEPES, 0.8 mM MgCl 2 , 1.8 CaCl 2 , 10 mM glucose and 30 mM sucrose, adjusted to pH 7.4 with 1M NaOH) and was constantly perused at a rate of 1 ml/min. Recordings were performed at room temperature (20- 22 °C) using an Axopatch 200B amplifier (Axon Instruments Ltd., Foster City, CA).

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Claims (15)

  1. Ein heterocyclisches Derivat gemäß der Formel I
    Figure imgb0145
     wobei
    L1 O, NR5, (CR6R7)m, CO oder SO2 ist,
    L2 NR8SO2 oder SO2NR9 ist,
    R1 H, C1-6-Alkyl, C3-8-Cycloalkyl, C1-6-Alkyloxy, Halogen, CN, COR10, SR11, SOR12, SO2R13, NHCOR14, NHSO2R15, NHCOR16 oder CONHR17 ist, wobei das C1-6-Alkyl, C3-8-Cycloalkyl und C1-6-Alkyloxy gegebenenfalls substituiert sind mit einem oder mehreren Halogenen,
    R2 C1-6-Alkyl, C3-8-Cycloalkyl, C1-6-Alkyloxy oder CN ist, wobei das C1-6-Alkyl, C3-8-Cycloalkyl und C1-6-Alkyloxy substituiert sind mit einem oder mehreren Resten, unabhängig ausgewählt aus Halogen, OH, C1-6-Alkyloxy, CN, NR18R19, COR20, SR21, SOR22, SO2R23, NHCOR2a, NHSO2R25, NHCOR26 und CONHR27, oder R2 zusammen mit X3, wobei X1 und X2 N oder CR31 sind und R31 H oder C1-6-Alkyl ist und X3 C ist, mit der Maßgabe, dass wenigstens eines von X1 - X3 N sein muss, einen 5- bis 7-gliedrigen ungesättigten carbocyclischen Ring bilden, der gegebenenfalls N umfasst,
    R3 H, C1-6-Alkyl, C3-8-Cycloalkyl, C1-6-Alkoxy, Halogen oder CN ist, wobei das C1-6-Alkyl, C3-8-Cycloalkyl und C1-6-Alkyloxy gegebenenfalls substituiert sind mit einem oder mehreren Halogenen,
    R4 H, C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-8-Cycloalkyl, C1-2-Alkyl-C3-8-cycloalkyl, NR28R29, C6-10-Aryl oder ein 5-9-gliedriges Heteroarylringsystem, das 1-2 Heteroatome, unabhängig ausgewählt aus O, S und N, umfasst, ist, wobei das C1-6-Alkyl, C3-8-Cycloalkyl, C6-10-Aryl und das 5-9-gliedrige Heteroarylringsystem gegebenenfalls substituiert sind mit einem oder mehreren Resten, unabhängig ausgewählt aus Halogen, C1-6-Alkyl, Hydroxy und C1-6-Alkyloxy, wobei das C1-6-Alkyl und C1-6-Alkyloxy gegebenenfalls substituiert sind mit 1-3 Halogenen,
    R5-R10 unabhängig H oder C1-6-Alkyl sind,
    R11-R16 unabhängig C1-6-Alkyl sind,
    R17 H oder C1-6-Alkyl ist,
    R18 und R19 unabhängig H oder C1-4-Alkyl, gegebenenfalls substituiert mit einem 5-9-gliedrigen Heteroarylringsystem, das 1-2 Heteroatome, unabhängig ausgewählt aus O, S und N, umfasst, sind oder R18 und R19 zusammen mit dem N, an das sie gebunden sind, einen 4-6-gliedrigen gesättigten oder ungesättigten heterocyclischen Ring bilden, der gegebenenfalls ein weiteres Heteroatom, ausgewählt aus O, S und N(R30)p, umfasst,
    R20 unabhängig H oder C1-4-Alkyl ist,
    R21-R26 unabhängig C1-4-Alkyl sind,
    R27 H oder C1-4-Alkyl ist,
    R28 und R29 unabhängig H oder C1-4-Alkyl sind, oder R28 und R29 zusammen mit dem N, an das sie gebunden sind, einen 4-6-gliedrigen gesättigten oder ungesättigten heterocyclischen Ring bilden, der gegebenenfalls ein weiteres Heteroatom, ausgewählt aus O, S und N, umfasst,
    R30 H oder C1-4-Alkyl ist,
    m 1-2 ist,
    n 1-3 ist,
    p 0 oder 1 ist,
    wenn R2 zusammen mit X3, wobei X3 C ist, keinen 5- bis 7-gliedrigen ungesättigten carbocyclischen Ring bildet, der gegebenenfalls ein N umfasst, das Fragment
    Figure imgb0146
     ausgewählt ist aus:
    Figure imgb0147
    Figure imgb0148
     Y1-Y3 unabhängig CR32 oder N sind, mit der Maßgabe, dass nur 1 von Y1-Y3 N sein kann, wobei R32 H, C1-6-Alkyl, C3-8-Cycloalkyl, C1-6-Alkyloxy, Halogen oder CN ist, wobei das C1-6-Alkyl, C3-8-Cycloalkyl und C1-6-Alkyloxy gegebenenfalls substituiert sind mit einem oder mehreren Halogenen,
    oder ein pharmazeutisch annehmbares Salz oder Solvat davon.
  2. Das heterocyclische Derivat gemäß Anspruch 1, wobei R1 CF3 ist.
  3. Das heterocyclische Derivat gemäß Anspruch 1 oder Anspruch 2, wobei R2 Methyl, gegebenenfalls substituiert mit Halogen, Hydroxy oder NR18R19, wobei R18 und R19 die oben definierten Bedeutungen besitzen, ist.
  4. Das heterocyclische Derivat gemäß einem der Ansprüche 1-3, wobei R3 H ist.
  5. Das heterocyclische Derivat gemäß einem der Ansprüche 1-4, wobei R4 Methyl, Ethyl, Isopropyl oder tert-Butyl ist, wobei das Methyl, Ethyl, Isopropyl und tert-Butyl gegebenenfalls mit einem oder mehreren Halogenen substituiert sind.
  6. Das heterocyclische Derivat gemäß einem der Ansprüche 1-5, wobei X1 und X2 N sind und X3 CH ist.
  7. Das heterocyclische Derivat gemäß einem der Ansprüche 1-6, wobei L1 CH2 ist.
  8. Das heterocyclische Derivat gemäß einem der Ansprüche 1-7, wobei R18 und R19 unabhängig H oder C1-4-Alkyl sind.
  9. Das heterocyclische Derivat gemäß einem der Ansprüche 1-7, wobei Y1-Y3 CH sind.
  10. Das heterocyclische Derivat gemäß einem der Ansprüche 1-8, wobei L2 NHSO2 ist.
  11. Ein heterocyclisches Derivat gemäß Anspruch 1, ausgewählt aus:
    Figure imgb0149
    Figure imgb0150
    Figure imgb0151
    Figure imgb0152
    Figure imgb0153
    Figure imgb0154
    Figure imgb0155
    Figure imgb0156
    Figure imgb0157
    Figure imgb0158
    Figure imgb0159
    Figure imgb0160
    Figure imgb0161
     und
    Figure imgb0162
     oder ein pharmazeutisch annehmbares Salz oder Solvat davon.
  12. Ein heterocyclisches Derivat gemäß einem der Ansprüche 1-11 zur Verwendung in der Therapie.
  13. Ein heterocyclisches Derivat gemäß einem der Ansprüche 1-11 zur Verwendung bei der Behandlung oder Prävention von psychiatrischen Erkrankungen, bei denen eine Verstärkung der durch AMPA-Rezeptoren vermittelten synaptischen Reaktionen benötigt wird.
  14. Eine pharmazeutische Zusammensetzung, die ein heterocyclisches Derivat gemäß einem der Ansprüche 1-11 im Gemisch mit einem pharmazeutisch annehmbaren Hilfsstoff umfasst.
  15. Verwendung eines heterocyclischen Derivats gemäß einem der Ansprüche 1-11 zur Herstellung eines Medikaments zur Behandlung oder Prävention von psychiatrischen Erkrankungen, bei denen eine Verstärkung der durch AMPA-Rezeptoren vermittelten synaptischen Reaktionen benötigt wird.
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